Composition and method for reducing the risk or progression of cardiovascular, glaucoma and tardive dyskinesia diseases

ABSTRACT

Elevated levels of homocysteine have been implicated as an important risk factor for cardiovascular and other diseases. A composition for decreasing levels of plasma homocysteine and a method for administering the composition are provided the composition containing dextromethorphan (DM), folic acid and vitamins B 6  and B 12 . The composition provides a synergistic therapeutic effect so that lower amounts of the above ingredients may be employed to minimize any undesirable side effects caused by the use of high levels of a component such as DM. Preferred compositions for cardiovascular diseases further include lecithin, vitamin E, beta-carotene, procyanidins/flavonoids, trimethylglycine, garlic oil and minerals. Other compositions for treating glaucoma include bilberry, bioflavonoids and beta-carotene and for treating tardive dyskinesia include an antioxidant such as grape seed extract and pine bark extract, lecithin and oligomeric proanthocyanidins. The compositions may be administered using any suitable means such as orally or intravenous.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a division of co-pending U.S. ApplicationSer. No. 09/845,141, filed on Apr. 30, 2001, and entitled, “Compositionand Method for Reducing the Risk or Progression of Cardiovascular,Glaucoma and Tardive Dyskinesia Diseases”, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a composition and method forreducing the risk or progression of cardiovascular, glaucoma and tardivedyskinesia diseases and, more particularly, to a composition containinga number of ingredients which are present in amounts lower than amountsconsidered harmful to the body but which act synergistically to provideenhanced disease inhibition.

[0004] 2. Description of Related Art

[0005] Cardiovascular disease is the most frequent cause of death inindustrialized countries. Atherosclerosis (AS) is the principal cause ofcardiovascular disease. AS is a disease of the intima of the arteriesthat leads to fatty lesions called artheromatous plaques on the insidesurface of the arteries. This deposit of fat and cholesterol narrows thearteries, and often becomes calcified, providing sites for abnormalblood clots to form, leading to high blood pressure, heart attacks andstrokes.

[0006] Elevated plasma homocysteine (Hcy) concentrations have repeatedlybeen associated with increased vascular risk. Hcy causes cells todecrease their production of clot preventing and clot dissolvingsubstances and increases production of clot promoting substances. Hcy isan intermediate sulfhydryl alpha-amino acid formed during conversion ofmethionine to cysteine.

[0007] The buildup of Hcy in the body leads to overproduction ofhomocysteine thiolactone that causes low density lipoprotein (LDL) tobecome aggregated, and start to form plaque on the artery walls. Highlyreactive oxygen radicals accumulate within this plaque resulting indamage to the lining cells of arteries, promoting blood clot formationand stimulating growth of arterial muscle cells which form fiberoustissue, mucoid matrix and degenerative elastic tissue (McCully K. TheHomocysteine Revolution, Keats Publishers, Lincolnwood Ill).

[0008] Thus, the presence of Hcy in the body has come to be a predictorof heart attacks, strokes, deep vein thrombosis and other circulatoryproblems. Evidence from The Life Extension Foundation indicates there isno “safe” normal range for Hcy. However, epidemiological data revealsthat Hcy levels above 6.3 cause a steep progressive risk of heartattack. A method of lowering Hcy would prevent and/or inhibit theseserious problems.

[0009] Dextromethorphan (DM) has recently been shown to decrease thelevels of Hcy as discussed in U.S. Pat. No. 6,025,369. The amount of DMnecessary to reduce Hcy to safe levels can cause undesirable sideeffects however.

[0010] Hcy and its degradation products are putative neurotransmittersand agonists at the N-methyl-D-aspartate (NMDA) receptor (Neuroreport2000, August 21; 11(12):2749-52). It has been shown that Hcy acts as anagonist at the glutamine binding side of the NMDA receptor (one type ofexcitatory amino acid receptor). Dextromethorphan (DM), a widely usedOTC antitussive agent, is a noncompetitive antagonist of the NMDAreceptor and is protective against the adverse effect of Hcy and itsmetabolites. DM, the d-isomer of the opiate agonist levorphanol, hasnone of the analgesic or sedative effects associated with the opiates.DM, acting as an antagonist at NMDA receptors, suppress the transmissionof nerve impulses and nerve signals mediated through NMDA receptors. Inaddition, DM has also been reported to suppress activity at neuronalcalcium channels.

[0011] Dextromethorphan and other NMDA receptor antagonists are knownfor treating glaucoma as discussed in U.S. Pat. No. 5,922,773 issued onJul. 13, 1999 to Lipton et al. and for treating tardive dyskinesia asshown in U.S. Pat. No. 5,866,585 issued on Feb. 2, 1999 to Fogel. Bothpatents are hereby incorporated by reference.

[0012] Vitamin supplements of folic acid, B₆ and B₁₂ have been shown tobe useful in lowering Hcy but there is evidence that for some elderlypeople it is not sufficient to keep the level of Hcy low enough to beout of the danger zone.

[0013] Bearing in mind the problems and deficiencies of the prior art,it is therefore an object of the present invention to provide acomposition for reducing the risk or progression of cardiovasculardiseases.

[0014] It is another object of the present invention to provide acomposition for reducing the risk or progression of glaucoma.

[0015] A further object of the invention is to provide a composition forreducing the risk or progression of tardive dyskinesia disease.

[0016] It is yet another object of the present invention to provide amethod for reducing the risk or progression of cardiovascular diseasesin a person by administering to the person a composition of theinvention.

[0017] Another object of the invention is to provide a method forreducing the risk or progression of glaucoma by administering to aperson a composition according to the invention.

[0018] An additional object of the invention is to provide a method forreducing the risk or progression of tardive dyskinesia diseases byadministering to a person a composition of the invention.

[0019] Still other objects and advantages of the invention will in partbe obvious and will in part be apparent from the specification.

SUMMARY OF THE INVENTION

[0020] The above and other objects, which will be apparent to thoseskilled in art, are achieved in the present invention which is directedto a composition comprising a mixture of ingredients and a method forusing the composition to reduce the risk or progression ofcardiovascular, glaucoma and tardive dyskinesia diseases. Thecomposition comprises a mixture of ingredients which act synergisticallyto provide the desired therapeutic effect. Broadly stated, levels ofhomocysteine are decreased in the plasma using known ingredients whichare present in amounts below the amount which would cause harmfuleffects in the body yet still provide the desired therapeutic effects.Dextromethorphan (DM) in combination with folic acid, vitamin B₆ andvitamin B₁₂ are essential ingredients of the composition. Preferredcompositions contain one or more of lecithin, vitamin E, beta-carotene,phytochemicals (e.g., proanthocyanidins, cyanidin, procyanidin,flavonoids, bioflavonoids), ginkgo biloba, trimethylglycine, garlic oil,vinpocetine, omega-3-oils, pantothenic acid, vitamin B₃, herbs such askava and minerals, especially selenium, zinc, magnesium and calcium.

[0021] It is also preferred to employ in the composition a free radicalinhibitor/antioxidant such as butylated hydroxytoluene (BHT) to protectthe amino group in DM from oxidation and to provide a longer plasmalevel of DM.

[0022] In another aspect of the invention the composition may be usedfor preventing and/or treating glaucoma and damage to retinal ganglioncells using the composition of the invention further preferablyincluding bilberry, bioflavonoids and beta-carotene and also oligomericproanthocyanidins (OPC), vinpocetine and omega-3-oils.

[0023] In still another aspect of the invention the composition may beused for preventing and/or treating tardive dyskinesia using thecomposition of the invention further including antioxidants such asgrape seed extract and pine bark extract, lecithin and oligomericproanthocyanidins and also pantothenic acid, vitamin B₃, omega-3-oilsand herbs such as kava.

[0024] In another aspect of the invention a method is provided forreducing the risk of or progression of cardiovascular, glaucoma andtardive dyskinesia diseases wherein the composition of the invention isadministered by oral, sublingual, buccal, transdermal and intramuscularand intravenous means. Oral compositions may be formed into a soft-gelarticle, capsule, tablets, tablet with coating, sustained release orgranular product.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

[0025] The essence of this invention is to provide a compositioncontaining a combination of ingredients which composition whenadministered to a person reduces the risk or progression ofcardiovascular, glaucoma and tardive dyskinesia diseases by asynergistic action of the individual ingredients of the composition tolower Hcy levels in the body. Broadly stated, DM in combination withfolic acid, vitamin B₆ and vitamin B₁₂ and preferably in combinationwith one or more of the following: lecithin (choline), phytochemicals,Vitamin A, preferably beta-carotene, vitamin E, ginkgo biloba, garlicoil, vinpocetine, omega-3-oils, pantothenic acid, vitamin B₃, herbs suchas kava, trimethylglycine and minerals, provide such a therapeuticcomposition. The composition results in lowering of the Hcy in the bloodwithout the side effects of using one or more or ingredients at levelswhich have adverse side effects in the body.

[0026] A N-methyl-D-aspartate antagonist is required in the compositionas disclosed in U.S. Pat. No. 6,025,369 and of the disclosed antoginistsdextromethorphan (DM) is the highly preferred ingredient in thecomposition of the invention. U.S. Pat. No. 6,025,369, supra, describesthe action of DM to lower Hcy levels and the patent is herebyincorporated by reference. Side effects at high doses of DM includedrowsiness, nausea and decreased coordination. Toxic high doses havealso been described in the literature. DM in amounts of greater than 400mg are considered to have undesirable side effects. In the compositionof the invention DM in amounts of about 5 to 360 mg, preferably 30-120mg in a single daily dose is preferred. The composition of the inventionis typically taken once daily and the following ingredient amounts arebased on a daily dosage.

[0027] With regard to the vitamins in the composition of the presentinvention, this will depend somewhat on the size, age, gender and healthof the patient. Speaking generally, the vitamins will normally be fromabout 5% to about 2,000% of the RDA for that vitamin, most often fromabout 25% to about 1,000% of the RDA. Of course, the RDA can varyconsiderably with the factors illustrated above. Almost, any acceptedvitamin may be included in the present compositions, for example,vitamins A, D, E, K, thiamin, ribloflavin, niacin, niacinamide (B₃), B₆,folate, B₁₂, biotin and pantothenic acid can all be included.

[0028] An inverse relationship has been observed between plasma folateand vitamin B₁₂ and plasma Hcy levels. Supplementation with these twovitamins leads to a significant decrease in Hcy levels. A significantdecrease in the rate of the progression of carotid plaque in coronaryheart disease patients has been reported with a supplement of 2.5 mgfolate, 25 mg vitamin B₆ and 150 μg vitamin B₁₂ daily.

[0029] The essential vitamins in the composition are B₆, B₁₂, andfolate, with vitamins E and A also being highly preferred.

[0030] The composition contains vitamin E at about 100 to about 600 IU,preferably 400 IU, vitamin B₆ at about 2 mg to about 100 mg, preferably6 to 25 mg, folate at about 0.5 to about 10 mg, preferably 1 to 5 mg,and vitamin B₁₂ at about 0.01 to about 5 mg, preferably 0.1 to 3 mg.

[0031] Vitamin A precursors (provitamin A, carotenoids) can also be usedincluding β-carotene, α-carotene, cryptoxanthine and the like. Thevitamin A esters and β-carotene are highly preferred forms of vitamin A.d-α-Tocopherol and its esters are highly preferred as a source forvitamin E. Other sources of vitamin E include β-tocopherol,γ-tocopherol, the tocotrienols and their esters, tocopheryl nicotinate,and the like. Vitamin B₆ can be selected from hydrochloride salts or5′-phosphates of pyridoxine, pyridoxamine or pyridoxal. The preferredvitamin B₆ is pyridoxine hydrochloride. The folate can be in the form offolic acid, mono and polyglutamyl folates, dihydro and tetrahydrofolates, methyl and formyl folates. Folic acid is a highly preferredform of folate. Sources of vitamin. B₁₂ are, for example,cyanocobalamin, methylcobalamin, adenosylcobalamin, hydroxocobalamin andthe like. Cyanocobalamin is highly preferred.

[0032] Vitamin A, preferably Beta-carotene, is employed at about 5,000to 25,000 IU, preferably 10,000 to 25,000 IU.

[0033] Evidence suggests that lecithin reduces the risk ofcardiovascular diseases by inhibiting intestinal absorption ofcholesterol and bile acids and favorably affecting lipoprotein levels.Fatty deposits containing cholesterol which thicken the arterial wallscause atherosclerosis, or hardening of the arteries. Lecithin, anemulsifier, helps clear the arteries of these deposits. Lecithin alsodemonstrates antioxidant activities, preventing free radical damage inthe arteries. Lecithin and the choline component of lecithin, play anumber of roles in cardiac function. Choline participates in themetabolism of Hcy. Choline or lecithin can reduce Hcy levels and it hasbeen reported that like folic acid, choline is involved in metabolizingHcy and has been shown to be partially effective in lowering Hcy inhumans. The disease tardive dyskinesia, associated with a malfunction ofcholinergic nerve transmission has been reported to be treatable withlecithin, a source of choline. Lecithin may be employed in an amount of300 to 2500 mg, preferably 600 to 1800 mg and it is preferred thatlecithin be used rather than choline.

[0034] The herb Ginkgo biloba is a preferred ingredient in thecomposition because it has been shown to help prevent and treat strokeand heart disease. Its properties include antioxidant, anti-inflammatoryand a toner of blood vessels. Other herbs such as kava are alsopreferred for use in the composition. Amounts of about 20 to 200 mg,preferably 40 to 120 mg, are used.

[0035] Garlic oil is used in the composition because of its knownability to lower cholesterol, lower high blood pressure and aid inimproving circulation. An amount of 50 to 500 mg, preferably 100 to 400mg, may be employed.

[0036] Trimethylglycine may be used in amounts of 50 to 1,000 mg,preferably 100 to 500 mg and is useful in the methylation ofhomocysteine.

[0037] The mineral supplement component of the compositions of thepresent invention comprises sources selected from calcium, phosphorus,magnesium, iron, zinc, iodine, selenium, copper, manganese, fluoride,chromium, molybdenum, potassium, and chloride, preferably selenium,zinc, magnesium and calcium. The mineral sources are preferably presentin an amount of at least 10% of the RDA of these minerals, and morepreferably, at least 30% of the RDA per unit dose of the finishedcomposition.

[0038] The amount of the above minerals in the composition is forcalcium 200 to 1500 mg, preferably 400 to 800 mg; magnesium 100 to 500mg, preferably 200 to 400 mg; zinc 10 to 100 mg, preferably 15 to 50 mg;and for selenium 50 to 200 μg, preferably 100 to 200 μg.

[0039] The source of the mineral salt can be any of the well known saltsincluding carbonate, oxide, hydroxide, chloride, sulfate, phosphate,gluconate, lactate, fumarate, citrate, malate, amino acids and the likefor the cationic minerals and potassium, calcium, magnesium and the likefor the anionic minerals.

[0040] As discussed in U.S. Pat. No. 6,025,369, supra, the basis of thatpatent is that the gross effects of homocysteine on vascular smoothmuscle cells is mediated through a NMDA-like glutamate gated calcium ionchannel receptor. Based on this finding the growth effects ofhomocysteine can be blocked through the use of NMDA receptiveantagonists.

[0041] Thus, the invention in the '369 patent comprises a new class ofdrugs for treating and prevention of atherosclerosis and these drugs actto inhibit the cell biochemical physiological actions of homocysteineactivated homocysteine receptor. One class of drugs which effectivelyaccomplish this objective includes those which are NMDA receptorblockers.

[0042] A number of NMDA receptor blockers are cited in the patent andthe preferred compound are the morphinans which include dextromethorphanwhich has the general formula:

[0043] In the preferred embodiment, dextromethorphan, R₁ is methyl, R₃is methoxy. For dextrorphan R₃ is hydroxy.

[0044] While other of the NMDA antagonists as noted in the Rosenquist etal. '369 patent and in the Lipton et al. and Fogel patents, supra, maybe used, DM is preferred. Any other NMDA receptor antagonists may beused and other compounds include amantadine derivatives (e.g.,memantine, amantadine and rimantadine).

[0045] The present composition also preferably contains a combination ofbotanical compounds, e.g., phytochemicals, in amounts of about 20 to 500mg, preferably 50 to 300 mg.

[0046] Phytochemicals may be broadly defined as chemicals derived fromplants and include plant sterols, flavonoids and sulfur containingcompounds. Plant sterols include sitosterol, stigmasterol andcampestrol. Flavonoids are compounds with varied chemical structurespresent in fruits, vegetables, nuts and seeds. The major flavonoidcategories are flavonoids, flavones, catechins, flavonones andanthocyanidins. Naturally occurring sulfur compounds (the allium family)are found in garlic, onions and leeks.

[0047] Flavonoids is a generic term for a group of aromatic oxygenheterocyclic compounds derived from 2-phenylbenzopyran or its2,3-dehydro derivative. They are widely distributed in higher plants andthe subgroup is the anthocyanidins. Another subgroup, referred to asVitamin P activity, are called bioflavonoids and high concentrations canbe obtained from citrus fruits.

[0048] Bioflavonoids, obtained from a variety of plant extracts, havebeen shown to exhibit antioxidant activity and to improve cardiacfunction.

[0049] Proanthocycanidins are often called condensed tannins and arefound in plants and are generally oligomers or polymers of flavonoidunits (e.g., flavan-3-ol) linked by carbon-carbon bonds not susceptibleto cleavage by hydrolysis. The most common anthocyanidins are cyanidin(flavan-3-ol), from procyanidin) and delphinidin (from prodelphinidin).Proanthocyanidins normally contain 2 to 50 or greater flavonoid units.

[0050] Phytochemicals included in the present compositions includebioflavonoids, such as for example, mono-acetyl-vitexinrhamnoside,rutin, luteolin-7-glucoside, hyperoside, and preferably quercetin and/orcatechin. Preferably, the composition of the present invention containcombinations of various flavonoids such as catechin and/or quercetin.The bioflavonoids can be added to the present composition in purifiedform or as part of a plant or other extract, for example. Amounts ofabout 5 to 500 mg, preferably 10 to 100 mg are used, especially in theglaucoma compositions.

[0051] Oligomeric proanthocyanidins (OPC) type of procyanidins (a typeof flavonoid from grape seed extract or pine bark extract) have beenshown to reduce platelet aggregation, to prevent free radical damage inthe arteries and the brain, and to treat tardive dyskinesia (for whichthere are no effective drugs). Vitamin E and beta-carotene are knownantioxidants which are added to the composition of our invention toprevent free radical damage to the arteries and to prevent lipidperoxidation. An amount of OPC is used at about 10 to 300 mg, preferably50 to 100 mg, especially for the glaucoma and tardive dyskinesiacompositions.

[0052] Bilberry is an antioxidant and is used especially in the glaucomacomposition in an amount of about 10 to 200 mg, preferably 20 to 120 mg.

[0053] The phytochemical component of the composition of the presentinvention may also include at least one of procyanidin or cyanidin andpreferably, contains a mixture of procyanidin and cyanidin. Thesephytochemicals have an antioxidant effect and have been demonstrated toprotect vascular endothelial cells from oxidant injury. The procyanidinand cyanidin component of the present composition may be added as amixture of both compounds or each may be added separately, in purifiedform or as an extract. In a preferred embodiment, procyanidin andcyanidin are added as a mixture and most preferably are obtained as anextract from grape seed, pine bark or other plant containing sufficientamounts of these compounds. Amounts of 10 to 300 mg, preferably 50 to150 mg are used.

[0054] Herbs useful in the compositions of the invention include kavaand may be used in amounts of 10 to 500 mg, preferably 40 to 200 mg.

[0055] In the glaucoma composition bilberry, bioflavonoids,beta-carotene and oligomeric proanthocyanidins are preferably includedin the above composition. Other components include, vinpocetine in anamount of about 1 to 10 mg, preferably 2.5 to 5 mg. Omega-3-oils, suchas fish oil are also preferred in amounts of about 0.1 to 4 g,preferably 0.5 to 2 g.

[0056] In the tardive dyskinesia composition an antioxidant such asgrape seed extract and/or pine bark extract, lecithin and oligomericproanthocyanidins and herbs are preferably added to the abovecomposition. Other components include panthothenic acid in an amount ofabout 5 to 250 mg, preferably 10 to 50 mg, a herb such as kava in anamount of about 10 to 100 mg, preferably 25 to 70 mg, vitamin B₃ in anamount of about 10 to 100, preferably 20 to 50 mg, and omega-3-oils inan amount of about 0.1 to 4 g, preferably 0.5 to 2 g. Kavalactone is theactive chemical in kava.

[0057] While the present invention has been particularly described, inconjunction with a specific preferred embodiment, it is evident thatmany alternatives, modifications and variations will be apparent tothose skilled in the art in light of the foregoing description. It istherefore contemplated that the appended claims will embrace any suchalternatives, modifications and variations as falling within the truescope and spirit of the present invention.

Thus, having described the invention, what is claimed is:
 1. Acomposition for reducing the risk or progression of cardiovasculardisease comprising: dextromethorphan; folic acid or folate; vitamin B₆;and vitamin B₁₂.
 2. The composition of claim 1 wherein the compositionincludes lecithin and vitamin E.
 3. The composition of claim 2 whereinthe composition includes beta-carotene.
 4. The composition of claim 3wherein the composition includes a compound selected from the groupconsisting of procyanidins, flavonoids, oligomeric proanthocyanidins andmixtures thereof.
 5. The composition of claim 4 wherein the compositionincludes trimethylglycine and ginkgo biloba.
 6. The composition of claim5 wherein the composition includes garlic oil and minerals.
 7. A methodof reducing the risk or progression of cardiovascular disease comprisingadministering to a person in need thereof the composition of claim
 1. 8.A method of reducing the risk or progression of cardiovascular diseasecomprising administering to a person in need thereof the composition ofclaim
 2. 9. A method of reducing the risk or progression ofcardiovascular disease comprising administering to a person in needthereof the composition of claim
 3. 10. A method of reducing the risk orprogression of cardiovascular disease comprising administering to aperson in need thereof the composition of claim
 4. 11. A method ofreducing the risk or progression of cardiovascular disease comprisingadministering to a person in need thereof the composition of claim 5.12. A method of reducing the risk or progression of cardiovasculardisease comprising administering to a person in need thereof thecomposition of claim
 6. 13. A composition for reducing the risk orprogression of glaucoma comprising: dextromethorphan; folic acid orfolate; vitamin B₆; and vitamin B₁₂; bilberry; bioflavonoids; andbeta-carotene
 14. The composition of claim 13 further includingoligomeric proanthocyanidins.
 15. The composition of claim 14 furtherincluding vinpocetine.
 16. The composition of claim 15 further includingomega-3-oils.
 17. A method for reducing the risk or progression ofglaucoma comprising administering to a person in need thereof thecomposition of claim
 13. 18. A method for reducing the risk orprogression of glaucoma comprising administering to a person in needthereof the composition of claim
 14. 19. A method for reducing the riskor progression of glaucoma comprising administering to a person in needthereof the composition of claim
 15. 20. A composition for reducing therisk or progression of tardive dyskinesia disease comprising:dextromethorphan; folic acid or folate; vitamin B₆; and vitamin B₁₂;lecithin; an antioxidant;and oligomeric proanthocyanidins.
 21. Thecomposition of claim 20 further including pantothenic acid.
 22. Thecomposition of claim 21 further including kava.
 23. The composition ofclaim 22 further including omega-3-oils.
 24. The composition of claim 23further including vitamin B₃.
 25. A method of reducing the risk ofprogression of tardive dyskinesia disease comprising administering to aperson in need thereof the composition of claim
 20. 26. A method ofreducing the risk of progression of tardive dyskinesia diseasecomprising administering to a person in need thereof the composition ofclaim
 21. 27. A method of reducing the risk of progression of tardivedyskinesia disease comprising administering to a person in need thereofthe composition of claim
 22. 28. A method of reducing the risk ofprogression of tardive dyskinesia disease comprising administering to aperson in need thereof the composition of claim
 23. 29. A method ofreducing the risk of progression of tardive dyskinesia diseasecomprising administering to a person in need thereof the composition ofclaim 24.